Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_000277.2(PAH):c.250G>T (p.Asp84Tyr)

CA229500

102639 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: fc7cd29b-7604-4db2-9477-5b5ad6389513

Approved on: 2023-12-30

Published on: 2023-12-30

HGVS expressions

NM_000277.2:c.250G>T

NM_000277.2(PAH):c.250G>T (p.Asp84Tyr)

NC_000012.12:g.102894837C>A

CM000674.2:g.102894837C>A

NC_000012.11:g.103288615C>A

CM000674.1:g.103288615C>A

NC_000012.10:g.101812745C>A

NG_008690.1:g.27766G>T

NG_008690.2:g.68574G>T

ENST00000553106.6:c.250G>T

ENST00000307000.7:c.235G>T

ENST00000546844.1:c.250G>T

ENST00000548677.2:n.337G>T

ENST00000548928.1:n.172G>T

ENST00000549111.5:n.346G>T

ENST00000550978.6:c.234G>T

ENST00000551337.5:c.250G>T

ENST00000551988.5:n.339G>T

ENST00000553106.5:c.250G>T

NM_000277.1:c.250G>T

NM_001354304.1:c.250G>T

NM_000277.3:c.250G>T

NM_001354304.2:c.250G>T

NM_000277.3(PAH):c.250G>T (p.Asp84Tyr)

Pathogenic

PP3 PM3_Very Strong PP4_Moderate PM2_Supporting

Evidence Links 6

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.250G>T (p.Asp84Tyr) variant in PAH has been reported in multiple individuals with PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 9634518). This variant has an extremely low allele frequency (MAF=0.00002) in gnomAD. This variant was detected with multiple pathgenic variants: F39L (PMID:11328945), Y356X (PMID: 15503242), P281L (PMID: 23430918), R158Q (PMID: 19609714) (PM3_VS). Multiple lines of computational evidence support a deleterious effect (SIFT, PolyPhen-2, MutationTaster, REVEL=0.819) (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_VS, PM2_supporting, PP4_Moderate, PP3.

PP3

Multiple lines of computational evidence support a deleterious effect (SIFT, PolyPhen-2, MutationTaster, REVEL=0.819)

PM3_Very Strong

Detected with F39L (P) PMID:11328945, Y356X (P/LP) PMID: 15503242, P281L (P) PMID: 23430918, R158Q (P) PMID: 19609714

When available, parental DNA samples were sequenced to confirm trans configurations in compound heterozygotes and to distinguish homozygosity from hemizygosity. Patient 38: PAH allele 1 D84Y; PAH allele 2 Y356X (VarID 595, P/LP) PubMed:15503242

Maternal PAH genotype: F39L/D84Y (VarID605, pathogenic) PubMed:11328945

Patient genotype: [D84Y] + [R158Q] (VarID 587, pathogenic) PubMed:19609714

mutant PAH Genotype p.D84Y: p.P281L (VarID589, pathogenic) PubMed:23430918

PP4_Moderate

D84Y was detected in 1 patient with classic PKU. Exclusion of a defect in tetrahydrobiopterin metabolism. PMID: 9634518

Seven centers in France, Italy, Belgium, Germany, and Denmark participated in this collaborative study. In all patients, hyperphenylalaninemia had been detected by national mass screening programs, and PAH deficiency had been assessed after exclusion of a defect in tetrahydrobiopterin metabolism. D84Y was detected in 1 patient with classic PKU. PubMed:9634518

One hundred forty-nine patients enrolled in the Maternal PKU Collaborative Study were subjects. They all had normal blood tyrosine concentrations. D84Y was detected on 1 chromosome. PubMed:8659548

PM2_Supporting

Extremely low frequency in gnomAD (MAF=0.00002)

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